Autoimmunity is the cause of several common endocrine disorders. Graves' disease and nongoitrous hypothyroidism are examples of diseases caused by activating and inhibitory antibodies, respectively, to a G protein-coupled cell surface receptor (GPCR). The extracellular calcium-sensing receptor (CaR) is a GPCR that plays a crucial role in maintaining mineral ion homeostasis by virtue of its capacity to sense small changes in the extracellular ionized calcium concentration (Ca2+o). The physiological relevance of the CaR was established by the discovery of patients with activating or inactivating mutations that produce hypo- or hypercalcemic conditions, respectively. The former is termed autosomal dominant hypocalcemia (ADH) and the latter familial hypocalciuric hypercalcemia (FHH). Similar to inactivating or activating mutations, there might be patients with inactivating or activating antibodies to the CaR. Indeed, we recently described 4 patients with inactivating antibodies to the CaR, three of whom had a picture of FHH while one had biochemical findings more like primary hyperparathyroidism (PHPT). Surprisingly, further preliminary studies have identified inactivating antibodies in two individuals who had undergone removal of a parathyroid (PT) adenoma for a diagnosis of PHPT, raising the possibility that anti-CaR antibodies can contribute to the development of PHPT in a subset of patients. Additional preliminary studies have also identified two hypocalcemic individuals with activating antibodies to the receptor, who have a biochemical picture compatible with hypoparathyroidism. The overall goal of this proposal is to document that activating and inactivating CaR antibodies can cause forms of hypoparathyroidism and PTH-dependent hypercalcemia, respectively, that should be distinguished from other causes of these disorders and may be amenable to specific CaR-based medical therapy. The following aims are addressed at achieving this goal: (1) To identify and characterize inactivating antibodies to the CaR in persons with PTH-dependent hypercalcemia. (2) To identify and characterize activating antibodies to the CaR in persons with hypoparathyroidism. (3) To develop an animal model of activating and/or inactivating antibodies by immunization with the CaR's extracellular domain. [unreadable] [unreadable]